Cabozantinib for Advanced Urothelial Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01688999
• Collaborator: (none)
• Enrollment: 69
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 131.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Background:

• Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. However, studies have shown that prostate and ovarian tumors respond to it. Researchers want see if cabozantinib can be a safe and effective treatment for urothelial cancer.

Objectives:

• To test the safety and effectiveness of cabozantinib for advanced urothelial cancer.

Eligibility:

• Individuals at least 18 years of age who have advanced urothelial cancer that has not responded to standard treatments.

Design:

• Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor tissue samples will also be collected. Imaging studies will also be performed.

• Participants will take cabozantinib by mouth once per day on each day of a 28-day cycle.

• Treatment will be monitored with frequent blood tests and imaging studies.

• Participants will continue to take the study drug for as long as their cancer does not worsen and side effects are not too severe.

Condition or Disease	Intervention/Treatment	Phase
Urothelial Carcinoma; Urethral Neoplasms; Urinary Bladder Neoplasms; Kidney Neoplasms	Drug: Cabozantinib	Phase 2

Detailed Description

Background:

• In the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women with an estimated 69,250 new cases and 14,990 deaths in the year 2011

• There is no Food and Drug Administration (FDA)-approved second line drug for patients with metastatic Urothelial Cancer (UC)

• Multiple lines of evidence support targeting angiogenesis in UC

• In human bladder cancer, overexpression of tyrosine-protein kinase (c-Met)/Axl/platelet derived growth factor receptor- (PDGFR)-alpha or c-Met alone showed significant correlation with poor survival

• Cabozantinib is a new chemical entity that inhibits multiple receptor tyrosine kinases with growth-promoting and angiogenic properties.

• The primary targets of cabozantinib are mesenchymal epithelial transition factor (MET), vascular endothelial factor receptor 2 (VEGFR2), and rearranged during transfection (RET)

Objectives:

• To determine the response rate of cabozantinib in patients with progressive urothelial cancer who have received prior cytotoxic chemotherapy

Eligibility:

• Patients in cohort 1 must have a histologically confirmed diagnosis of metastatic, progressive urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

• Patients in cohort 2 must have a histologically confirmed diagnosis of bone only metastatic, urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.

• Patients in cohort 3 must have a histologically confirmed diagnosis of non-transitional cell carcinoma cancer (including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid) of the bladder, urethra, ureter, or renal pelvis.

• Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic chemotherapy regimen or agent. Patients may have received any number of prior cytotoxic agents.

• 18 years of age or older.

Design:

• A maximum of 71subjects will be enrolled in this open label, non-randomized, phase II trial of 60 mg each day of cabozantinib. Up to 50 patients will be accrued to cohort 1 (metastatic, progressive urothelial cancer. The remainder will be enrolled on exploratory cohorts 2 & 3, bone only metastatic urothelial disease and non transitional cell carcinoma (TCC) bladder cancer respectively, during the time the study is accruing patients for cohort 1. Note: Patients who tolerate cabozantinib at 60 mg daily during the first 2 cycles (first restaging time period) without (Bullet) grade 2 toxicity may undergo dose escalation to 80 mg daily at the discretion of the Principal Investigator.

• A Simon 2 stage design with alpha=0.05 and beta = 0.10 as acceptable error probabilities. Initially 21 subjects will be enrolled and followed for progression. If 2 or more of cohort 1 subjects experiences a response, enrollment will continue until a total of 41 evaluable subjects with progressive urothelial cancer have been entered. 2-3 patients per month may enroll on this trial; thus, 2 to 3 years is anticipated as the accrual period.

• Each patient will undergo response evaluation assessments with chest abdomen pelvis computed tomography (CAP CT) (or magnetic resonance imaging (MRI)) with or without 18F-Sodium Fluoride (Na18F) positron emission tomography (PET CT) every 8 weeks while on active protocol therapy starting at baseline. Patients will undergo investigational Fludeoxyglucose, (FDG) PET/CT and PET/MRI (optional) at baseline, week 4 and week 8.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Cabozantinib (XL184) in Patients With Advanced/Metastatic Urothelial Carcinoma
• Actual Study Start Date: Sep 11, 2012
• Actual Primary Completion Date: Dec 11, 2017
• Anticipated Study Completion Date: Sep 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cabozantinib Administered orally at a dose of 60 mg once daily on each day of a 28-day cycle.	Drug: Cabozantinib; 60 mg by mouth (PO) daily each 28 day cycle. Treatment continues until toxicity or disease progression.; Other Names: Cometriq

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Overall Response [Median follow-up was 61.2 months]

   Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

1. Overall Survival [Median follow-up was 61.2 months]

   Measure the timing from the study start until death.

2. Progression Free Survival [Median follow-up was 61.2 months]

   Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.

3. Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib [Median follow-up was 61.2 months]

   Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.

4. Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution [Median follow-up was 61.2 months]

   Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

Cohort 1 only (urothelial progressive disease)

• Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any Clinical Laboratory Improvement Amendments (CLIA) certified lab.

• Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.

• Patients must have at least one measurable site of disease

Cohort 2 only (Bone-only)

• Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Confirmation may be obtained from any CLIA certified lab.

• Patients must not have measurable progressive disease

• Patient must have appearance of at least one new bone lesion.

Cohort 3 (Rare histologies)

• Patient must have a histologically confirmed diagnosis of non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis including but not limited to squamous cell, neuroendocrine, adenocarcinoma including urachal and sarcomatoid. Confirmation may be obtained from any CLIA certified lab.

• Patients must have progressive metastatic disease. Progressive disease will be defined as new or progressive lesions on cross-sectional imaging.

• Patients must have at least one measurable site of disease

All cohorts

• Patients must have been previously treated, as defined by treatment with at least one prior cytotoxic regimen or agent.

• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of cabozantinib in patients <18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.

• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%

• Adequate organ function as defined by the following criteria:

• Hemoglobin greater than or equal to 9 g/dL

• Absolute neutrophil count (ANC) greater than or equal to 1500/microL

• Platelets greater than or equal to 75,000/L

• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) less than or equal to 3.0 times upper limit of normal (ULN); less than or equal to 5.0 times ULN in cases of liver metastases

• Total serum bilirubin less than or equal to 1.5 times the upper limit of normal (ULN). For subjects with known Gilberts disease or similar syndrome with slow conjugation of bilirubin, total bilirubin less than or equal to 3.0 mg/dL

• Serum creatinine less than or equal to 1.5 X institutional upper limits of normal or for patients with creatinine levels above 1.5 x institutional normal: creatinine clearance greater than or equal to 50 mL/min/1.73 m^2 by 24 hour urine collection or estimated creatinine clearance of greater than or equal to 50 mL/min. For creatinine clearance estimation , the Cockcroft and Gault equation should be used:

• Male: Creatinine Clearance (CrCl) (mL/min) = (140 - age) times wt (kg)/ (serum creatinine times 72)

• Female: Multiply above result by 0.85

• Urine protein/creatinine ratio (UPCR) less than or equal to 2

• Patient must be able to provide either archival tumor samples (haematoxylin and eosin (H&E) slides and one paraffin block or 10 unstained slides) or undergo tumor biopsy.

• Patient must be capable of understanding and complying with protocol requirements and is willing to give informed consent

• The effects of XL184 on the developing human fetus are unknown. For this reason and because tyrosine kinase inhibitors agents are known to be teratogenic, women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of XL184 administration.

Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s).

• Women of childbearing potential must have a negative pregnancy test at screening. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as amenorrhea greater than or equal to 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason.

EXCLUSION CRITERIA:

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.

• Prior treatment with cabozantinib

• Prior treatment with other small molecule inhibitors of Vascular Endothelial Growth Factor Receptors (VEGFR) within less than or equal to 2 years of study enrollment.

• The subject has received radiation therapy:

• to the thoracic cavity or gastrointestinal tract within 3 months before the first dose of study treatment

• to bone or brain metastasis within 14 days before the first dose of study treatment

• to any other site(s) within 28 days before the first dose of study treatment

• The subject has received radionuclide treatment within 6 weeks before the first dose of study treatment

• The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.

• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.

• The subject has not recovered to baseline or Common Terminology Criteria in Adverse Events (CTCAE). Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.

• The subject has a primary brain tumor

• The subject has active brain metastases, leptomeningeal or epidural disease (Note: Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain scans are not required to confirm eligibility.)

• The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test greater than or equal to 1.3 times the laboratory upper limit of normal (ULN) within 7 days before the first dose of study treatment.

• The subject requires treatment, in therapeutic doses, with oral anticoagulants such as warfarin prior to initiation of protocol therapy. Low dose aspirin (less than or equal to 81 mg/day), lowdose warfarin (less than or equal to 1 mg/day), and low molecular weight heparin (LMWH) are permitted. Subjects will be permitted to use anticoagulation as described if treatment is required while they are enrolled on the protocol.

• The subject requires chronic concomitant treatment of strong Cytochrome P450 3A4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort).

Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical reference texts such as the Physicians Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the counter medicine or herbal product.

• The subject has experienced any of the following within 3 months before the first dose of study treatment:

• clinically-significant hematemesis or gastrointestinal bleeding

• hemoptysis of greater than or equal to 0.5 teaspoon (greater than or equal to 2.5 mL) of red blood

• any other signs indicative of pulmonary hemorrhage

• The subject has tumor invading (or concern for invasion) major blood vessels

• Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the Investigator would make the patient inappropriate for entry into this study.

• The subject has evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.

• The subject is unable to swallow tablets

• The subject has a corrected Q wave, T wave (QT) interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before treatment initiation.

• The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.

• The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

• The subject has had within 2 years before the start of study treatment evidence of another malignancy which required systemic treatment

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study agents. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Andrea B Apolo, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 10, 2019
• Informed Consent Form - Jun 28, 2019

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page
• http://medicine.iupui.edu/clinpharm/ddis/

Publications

• Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49. doi: 10.3322/caac.20006. Epub 2009 May 27.
• McCaffrey JA, Hilton S, Mazumdar M, Sadan S, Kelly WK, Scher HI, Bajorin DF. Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol. 1997 May;15(5):1853-7.
• Vaughn DJ, Broome CM, Hussain M, Gutheil JC, Markowitz AB. Phase II trial of weekly paclitaxel in patients with previously treated advanced urothelial cancer. J Clin Oncol. 2002 Feb 15;20(4):937-40.

• Responsible Party: Andrea Apolo, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01688999
• Other Study ID Numbers: 120205; 12-C-0205
• First Posted: Sep 20, 2012
• Last Update Posted: Oct 6, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Andrea Apolo, M.D., Principal Investigator, National Cancer Institute (NCI): Kidney Cancer; Tyrosine Kinase Inhibitor; Bladder Cancer
• Additional relevant MeSH terms: Carcinoma; Neoplasms; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Kidney Neoplasms; Urethral Neoplasms

Study Results

Participant Flow

Arm/Group Title	Cohort 1 - (Urothelial Progressive Disease)	Cohort 2 (Bone-only)	Cohort 3 (Rare Histologies)
Arm/Group Description	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
Period Title: Overall Study
STARTED	50	6	13
COMPLETED	42	5	10
NOT COMPLETED	8	1	3

Baseline Characteristics

Arm/Group Title	Cohort 1 - (Urothelial Progressive Disease)	Cohort 2 (Bone-only)	Cohort 3 (Rare Histologies)	Total
Arm/Group Description	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.	Total of all reporting groups
Overall Participants	50	6	13	69
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	66	57	63
Sex: Female, Male (Count of Participants)
Female	16 32%	1 16.7%	4 30.8%	21 30.4%
Male	34 68%	5 83.3%	9 69.2%	48 69.6%
Race/Ethnicity, Customized (Count of Participants)
White	41 82%	5 83.3%	10 76.9%	56 81.2%
African American	4 8%	0 0%	3 23.1%	7 10.1%
Asian	2 4%	1 16.7%	0 0%	3 4.3%
Unknown	2 4%	0 0%	0 0%	2 2.9%
Region of Enrollment (participants) [Number]
United States	50 100%	6 100%	13 100%	69 100%
Primary Tumor Site (Count of Participants)
Bladder	30 60%	5 83.3%	12 92.3%	47 68.1%
Upper tract:renal pelvis or ureter	18 36%	0 0%	1 7.7%	19 27.5%
Bladder & upper tract	2 4%	1 16.7%	0 0%	3 4.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Overall Response
Description	Complete Response (CR) or Partial Response (PR) to Cabozantinib (XL184) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Time Frame	Median follow-up was 61.2 months

Outcome Measure Data

Analysis Population Description

42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.

Arm/Group Title	Cohort 1 - (Urothelial Progressive Disease)	Cohort 2 (Bone-only)	Cohort 3 (Rare Histologies)
Arm/Group Description	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
Measure Participants	42	5	10
Number (95% Confidence Interval) [percentage of participants]	19.1 38.2%	NA NaN	NA NaN

2. Secondary Outcome

Title	Overall Survival
Description	Measure the timing from the study start until death.
Time Frame	Median follow-up was 61.2 months

Outcome Measure Data

Analysis Population Description

42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.

Arm/Group Title	Cohort 1 - (Urothelial Progressive Disease)	Cohort 2 (Bone-only)	Cohort 3 (Rare Histologies)
Arm/Group Description	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
Measure Participants	42	5	10
Median (95% Confidence Interval) [Months]	8.1	9.3	5.8

3. Secondary Outcome

Title	Progression Free Survival
Description	Measure the timing of maintaining stable disease or partial response until disease progression assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions. Stable disease is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest um diameters while on study.
Time Frame	Median follow-up was 61.2 months

Outcome Measure Data

Analysis Population Description

42/50 were analyzed in cohort 1 because 5 participants withdrew, 2 were taken off study for adverse events and 1 was ineligible. In cohort 2, 5/6 patients were analyzed because 1 withdrew; and in cohort 3, 10/13 patients were analyzed because 1 withdrew and 2 were taken off study due to adverse events.

Arm/Group Title	Cohort 1 - (Urothelial Progressive Disease)	Cohort 2 (Bone-only)	Cohort 3 (Rare Histologies)
Arm/Group Description	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis.	Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
Measure Participants	42	5	10
Median (95% Confidence Interval) [Months]	3.7	5.3	2.9

4. Secondary Outcome

Title	Number of Participants With Grade 4 Toxicity Hypomagnesium Related to Cabozantinib
Description	Grade 4 toxicity hypomagnesium experienced by participants related to Cabozantinib. Grade 4 toxicity is life-threatening consequences; urgent intervention indicated.
Time Frame	Median follow-up was 61.2 months

Outcome Measure Data

Analysis Population Description

We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.

Arm/Group Title	All Participants
Arm/Group Description	Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
Measure Participants	68
Count of Participants [Participants]	2 4%

5. Secondary Outcome

Title	Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution
Description	Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	Median follow-up was 61.2 months

Outcome Measure Data

Analysis Population Description

We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.

Arm/Group Title	All Participants
Arm/Group Description	Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
Measure Participants	68
Count of Participants [Participants]	67 134%

Adverse Events

Time Frame	Median follow-up was 61.2 months
Adverse Event Reporting Description	All serious and non-serious adverse events are reported regardless of attribution. We did not group the adverse events by cohort because we did not expect the cohorts to experience different adverse events as they were all getting the same medication at the same dose. And 68/69 participants were analyzed because one participant was enrolled and deemed ineligible prior to treatment.
Arm/Group Title	All Participants
Arm/Group Description	Cohort 1 - (urothelial progressive disease) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Cohort 2 (Bone-only) Patients with bone-only urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. Cohort 3 (Rare histologies) Patients with non-transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis.
All Cause Mortality
	All Participants
	Affected / at Risk (%)	# Events
Total	66/68 (97.1%)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	66/68 (97.1%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other, pulmonary embolus	1/68 (1.5%)	1
Endocrine disorders
Endocrine disorders - Other, thyroiditis	1/68 (1.5%)	1
Gastrointestinal disorders
Abdominal pain	2/68 (2.9%)	2
Constipation	1/68 (1.5%)	1
Diarrhea	3/68 (4.4%)	4
Duodenal obstruction	1/68 (1.5%)	1
Gastric hemorrhage	1/68 (1.5%)	1
Mucositis oral	1/68 (1.5%)	1
Nausea	1/68 (1.5%)	1
Rectal fistula	1/68 (1.5%)	1
Toothache	1/68 (1.5%)	1
General disorders
Fatigue	6/68 (8.8%)	6
Pain	2/68 (2.9%)	5
Immune system disorders
Anaphylaxis	1/68 (1.5%)	1
Infections and infestations
Urinary tract infection	2/68 (2.9%)	2
Investigations
Alanine aminotransferase increased	3/68 (4.4%)	3
Alkaline phosphatase increased	4/68 (5.9%)	4
Aspartate aminotransferase increased	3/68 (4.4%)	4
Creatinine increased	1/68 (1.5%)	1
Lipase increased	1/68 (1.5%)	3
Lymphocyte count decreased	2/68 (2.9%)	2
Neutrophil count decreased	2/68 (2.9%)	4
Platelet count decreased	3/68 (4.4%)	3
Serum amylase increased	1/68 (1.5%)	2
White blood cell decreased	1/68 (1.5%)	1
Metabolism and nutrition disorders
Hypokalemia	1/68 (1.5%)	1
Hypomagnesemia	2/68 (2.9%)	6
Hyponatremia	2/68 (2.9%)	4
Hypophosphatemia	5/68 (7.4%)	13
Musculoskeletal and connective tissue disorders
Back pain	2/68 (2.9%)	2
Musculoskeletal and connective tissue disorder - Other, specify	1/68 (1.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	66/68 (97.1%)	66
Nervous system disorders
Stroke	1/68 (1.5%)	1
Renal and urinary disorders
Acute kidney injury	1/68 (1.5%)	1
Proteinuria	3/68 (4.4%)	3
Reproductive system and breast disorders
Pelvic pain	1/68 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Voice alteration	1/68 (1.5%)	1
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/68 (1.5%)	1
Vascular disorders
Hypertension	4/68 (5.9%)	4
Other (Not Including Serious) Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	67/68 (98.5%)
Blood and lymphatic system disorders
Anemia	21/68 (30.9%)	52
Blood and lymphatic system disorders - Other, hematemesis	1/68 (1.5%)	1
Cardiac disorders
Palpitations	2/68 (2.9%)	2
Sinus tachycardia	1/68 (1.5%)	1
Transient ischemic attacks	1/68 (1.5%)	1
Endocrine disorders
Endocrine disorders - Other, thyroiditis	1/68 (1.5%)	1
Hyperthyroidism	7/68 (10.3%)	8
Hypothyroidism	21/68 (30.9%)	27
Eye disorders
Eye pain	1/68 (1.5%)	2
Gastrointestinal disorders
Abdominal pain	9/68 (13.2%)	11
Anal pain	2/68 (2.9%)	2
Anal ulcer	1/68 (1.5%)	1
Bloating	2/68 (2.9%)	2
Constipation	17/68 (25%)	17
Diarrhea	35/68 (51.5%)	63
Dry mouth	5/68 (7.4%)	5
Dyspepsia	1/68 (1.5%)	1
Flatulence	1/68 (1.5%)	1
Gastroesophageal reflux disease	2/68 (2.9%)	2
Gastroparesis	2/68 (2.9%)	2
Gingival pain	1/68 (1.5%)	1
Hemorrhoids	3/68 (4.4%)	3
Mucositis oral	14/68 (20.6%)	19
Nausea	23/68 (33.8%)	26
Oral dysesthesia	2/68 (2.9%)	4
Oral pain	7/68 (10.3%)	7
Rectal fistula	1/68 (1.5%)	1
Rectal hemorrhage	3/68 (4.4%)	3
Rectal pain	2/68 (2.9%)	2
Tooth discoloration	1/68 (1.5%)	1
Toothache	1/68 (1.5%)	1
Vomiting	7/68 (10.3%)	10
General disorders
Chills	4/68 (5.9%)	4
Edema limbs	5/68 (7.4%)	5
Fatigue	28/68 (41.2%)	48
Fever	8/68 (11.8%)	9
Flu like symptoms	1/68 (1.5%)	1
Localized edema	1/68 (1.5%)	3
Malaise	1/68 (1.5%)	1
Pain	10/68 (14.7%)	11
Infections and infestations
Infections and infestations - Other, URI	1/68 (1.5%)	1
Laryngitis	1/68 (1.5%)	1
Lip infection	1/68 (1.5%)	1
Paronychia	1/68 (1.5%)	3
Pharyngitis	1/68 (1.5%)	1
Rhinitis infective	3/68 (4.4%)	4
Sinusitis	3/68 (4.4%)	3
Skin infection	3/68 (4.4%)	3
Stoma site infection	1/68 (1.5%)	2
Tooth infection	1/68 (1.5%)	1
Upper respiratory infection	4/68 (5.9%)	5
Urinary tract infection	7/68 (10.3%)	9
Wound infection	1/68 (1.5%)	1
Infections and infestations - Other, umbilical fungal infection	1/68 (1.5%)	1
Injury, poisoning and procedural complications
Fracture	1/68 (1.5%)	1
Injury, poisoning and procedural complications - Other, R. mediport	1/68 (1.5%)	1
Wound complication	1/68 (1.5%)	1
Investigations
Activated partial thromboplastin time prolonged	4/68 (5.9%)	6
Alanine aminotransferase increased	35/68 (51.5%)	59
Alkaline phosphatase increased	19/68 (27.9%)	28
Aspartate aminotransferase increased	37/68 (54.4%)	59
Blood bilirubin increased	1/68 (1.5%)	1
Creatinine increased	18/68 (26.5%)	40
GGT increased	4/68 (5.9%)	4
Lipase increased	8/68 (11.8%)	16
Lymphocyte count decreased	9/68 (13.2%)	13
Neutrophil count decreased	13/68 (19.1%)	23
Platelet count decreased	33/68 (48.5%)	52
Serum amylase increased	8/68 (11.8%)	18
Weight loss	7/68 (10.3%)	8
White blood cell decreased	22/68 (32.4%)	40
Metabolism and nutrition disorders
Anorexia	15/68 (22.1%)	19
Dehydration	2/68 (2.9%)	2
Hypercalcemia	1/68 (1.5%)	1
Hyperglycemia	5/68 (7.4%)	9
Hyperkalemia	1/68 (1.5%)	1
Hypermagnesemia	2/68 (2.9%)	2
Hypernatremia	1/68 (1.5%)	1
Hypoalbuminemia	15/68 (22.1%)	34
Hypocalcemia	11/68 (16.2%)	36
Hypoglycemia	4/68 (5.9%)	4
Hypokalemia	4/68 (5.9%)	6
Hypomagnesemia	13/68 (19.1%)	61
Hyponatremia	14/68 (20.6%)	22
Hypophosphatemia	29/68 (42.6%)	62
Musculoskeletal and connective tissue disorders
Abdominal soft tissue necrosis	1/68 (1.5%)	2
Arthralgia	4/68 (5.9%)	4
Arthritis	1/68 (1.5%)	1
Back pain	14/68 (20.6%)	15
Buttock pain	1/68 (1.5%)	1
Flank pain	5/68 (7.4%)	5
Musculoskeletal and connective tissue disorder - Other, specify	1/68 (1.5%)	1
Myalgia	4/68 (5.9%)	4
Neck pain	1/68 (1.5%)	2
Non-cardiac chest pain	4/68 (5.9%)	5
Pain in extremity	3/68 (4.4%)	4
Scalp pain	1/68 (1.5%)	1
Musculoskeletal and connective tissue disorder - Other, specify	1/68 (1.5%)	1
Musculoskeletal and connective tissue disorder - Other, specify	1/68 (1.5%)	1
Musculoskeletal and connective tissue disorder - Other, specify	2/68 (2.9%)	3
Musculoskeletal and connective tissue disorder - Other, thoracic muscle spasms	1/68 (1.5%)	1
Nervous system disorders
Concentration impairment	1/68 (1.5%)	1
Dizziness	9/68 (13.2%)	11
Dysgeusia	19/68 (27.9%)	20
Headache	4/68 (5.9%)	4
Memory impairment	1/68 (1.5%)	1
Paresthesia	1/68 (1.5%)	1
Peripheral sensory neuropathy	2/68 (2.9%)	2
Sinus pain	1/68 (1.5%)	1
Psychiatric disorders
Depression	1/68 (1.5%)	1
Insomnia	7/68 (10.3%)	7
Renal and urinary disorders
Bladder spasm	1/68 (1.5%)	1
Hematuria	14/68 (20.6%)	14
Proteinuria	6/68 (8.8%)	11
Urinary frequency	1/68 (1.5%)	1
Urinary incontinence	1/68 (1.5%)	1
Urinary tract pain	1/68 (1.5%)	1
Reproductive system and breast disorders
Genital edema	1/68 (1.5%)	1
Pelvic pain	3/68 (4.4%)	4
Scrotal pain	1/68 (1.5%)	1
Vaginal discharge	1/68 (1.5%)	6
Respiratory, thoracic and mediastinal disorders
Cough	2/68 (2.9%)	2
Dyspnea	7/68 (10.3%)	9
Epistaxis	2/68 (2.9%)	2
Hoarseness	10/68 (14.7%)	10
Laryngeal inflammation	3/68 (4.4%)	3
Nasal congestion	1/68 (1.5%)	1
Pneumothorax	1/68 (1.5%)	1
Postnasal drip	1/68 (1.5%)	1
Sore throat	4/68 (5.9%)	4
Voice alteration	4/68 (5.9%)	5
Skin and subcutaneous tissue disorders
Alopecia	7/68 (10.3%)	7
Dry skin	9/68 (13.2%)	9
Erythema multiforme	3/68 (4.4%)	3
Palmar-plantar erythrodysesthesia syndrome	37/68 (54.4%)	77
Pruritus	1/68 (1.5%)	1
Rash acneiform	7/68 (10.3%)	8
Rash maculo-papular	4/68 (5.9%)	4
Rash pustular	2/68 (2.9%)	3
Scrotal infection	3/68 (4.4%)	4
Skin and subcutaneous tissue disorders - Other, specify	1/68 (1.5%)	1
Skin hyperpigmentation	1/68 (1.5%)	1
Skin hypopigmentation	2/68 (2.9%)	2
Skin ulceration	3/68 (4.4%)	3
Skin and subcutaneous tissue disorders - Other, abrasion - lft. ankle	1/68 (1.5%)	1
Skin and subcutaneous tissue disorders - Other, fever blisters on lip	1/68 (1.5%)	1
Skin and subcutaneous tissue disorders - Other, Inguinal rash	1/68 (1.5%)	2
Skin and subcutaneous tissue disorders - Other, outer stoma bleeding	1/68 (1.5%)	2
Skin and subcutaneous tissue disorders - Other, Pustule R. buttock	1/68 (1.5%)	1
Skin and subcutaneous tissue disorders - Other, Scrotal erythema	2/68 (2.9%)	2
Skin and subcutaneous tissue disorders - Other, Stoma ileal conduit	1/68 (1.5%)	1
Vascular disorders
Hypertension	10/68 (14.7%)	11
Hypotension	1/68 (1.5%)	1
Thromboembolic event	4/68 (5.9%)	4
Vascular access complication	1/68 (1.5%)	1
Vascular disorders - Other, L. PE	1/68 (1.5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.